The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
The term “acute coronary syndromes” (“ACS”) has been applied to a group of coronary disorders that result from ischemic insult to the heart. Patients with ACS form a heterogeneous group, with differences in pathophysiology, clinical presentation, and risk for adverse events. Such patients present to the physician with conditions that span a continuum that includes unstable angina, non-ST-elevation non-Q wave myocardial infarction (“NST”-“MI”), ST-elevation non-Q wave MI, and transmural (Q-wave) MI. ACS is believed to result largely from thrombus deposition and growth within one or more coronary arteries, resulting in a partial or complete occlusion of the artery, and frequently involves rupture of the plaque, resulting in an ischemic injury. ACS may also be precipitated by a coronary vasospasm or increased myocardial demand. For review, see, e.g., Davies, Clin. Cardiol. 20 (Supp. I): 12–17 (1997).
The seriousness of ACS is underlined by the morbidity and mortality that follow the ischemic insult. For example, workers have estimated that within four to six weeks of presentation with ACS, the risk of death or a subsequent MI is 8–14%, and the rate of death, MI, or refractory ischemia is 15–25%. Theroux and Fuster, Circulation 97: 1195–1206 (1998) Given that the total number of deaths in the U.S. from acute MI is about 600,000, the search within the art for information that relates to the diagnosis, prognosis, and management of ACS has understandably been extensive. Several potential markers that may provide such information in certain patient populations have been identified, including circulating cardiac troponin levels (see, e.g., Antman et al., N. Eng. J. Med. 335: 1342–9 (1996); see also U.S. Pat. Nos. 6,147,688, 6,156,521, 5,947,124, and 5,795,725, each of which is hereby incorporated by reference in its entirety), ST-segment depression (see, e.g., Savonitto et al., JAMA 281: 707–13 (1999)), circulating creatine kinase levels (see, e.g., Alexander et al., Circulation (Suppl.) 1629 (1998)), and circulating c-reactive protein levels (see, e.g., Morrow et al., J. Am. Coll. Cardiol. 31: 1460–5 (1998)).
B-type natriuretic peptide (“BNP” or “BNP-32”) is a 32-amino acid neurohormone that is synthesized in ventricular myocardium and released into the circulation in response to ventricular dilation and pressure overload. The functions of BNP, like atrial natriuretic peptide, include natriuresis, vasodilation, inhibition of the renin-angiotensin-aldosterone axis, and inhibition of sympathetic nerve activity. The plasma concentration of BNP is elevated among patients with congestive heart failure (CHF), and increases in proportion to the degree of left ventricular dysfunction and the severity of CHF symptoms. For review, see, e.g., Wiese et al., Circulation 102: 3074–9 (2000); Yasue et al., Circulation 90: 195–203 (1994); Yoshimura et al., Circulation 87: 464–9 (1993); Stein and Levin, Am. Heart J. 135: 914–23 (1998); and Omland et al., Heart 76: 232–7 (1996).
The precursor to BNP is synthesized as a 108-amino acid molecule, referred to as “pre pro BNP,” that is proteolytically processed into a 76-amino acid N-terminal peptide (amino acids 1–76), referred to as “NT pro BNP” and the 32-amino acid mature hormone, referred to as BNP or BNP 32 (amino acids 77–108). It has been suggested that each of these species—NT pro-BNP, BNP-32, and the pre pro BNP—can circulate in human plasma. See, e.g., Tateyama et al., Biochem. Biophys. Res. Commun. 185: 760–7 (1992); Hunt et al., Biochem. Biophys. Res. Commun. 214: 1175–83 (1995). Pre pro BNP and NT pro BNP, and peptides which are derived from BNP, pre pro BNP and NT pro BNP that are present in the blood as a result of proteolyses of BNP, NT pro BNP and pre pro BNP, are collectively described herein as “markers related to or associated with BNP.”
Following the onset of acute MI, the plasma concentration of BNP has been shown to rise rapidly over the first 24 hours, and then to stabilize; patients with large infarcts may have a second peak in BNP concentration several days later. The concentration of BNP, when measured between 1 and 4 days following a transmural infarct, can provide prognostic information that is independent of the left ventricular ejection fraction (LVEF) and other important baseline variables. See, e.g., Talwar et al., Eur. Heart J. 21: 1514–21 (2000); Darbar et al., Am. J Cardiol. 78: 284–7 (1996); Richards et al., Heart 81: 114–20 (1999); Omland et al., Circulation 93: 1963–9 (1996); Arakawa et al., J. Am. Coll. Cardiol. 27: 1656–61 (1996); and Richards et al., Circulation 97: 1921–9 (1998).
To date, however, studies evaluating the prognostic implications of increased BNP concentration have been limited to patients with ST-elevation MI, and few data are available with regard to the prognostic implications of BNP following non ST-elevation acute coronary syndromes, including unstable angina and NST-MI. Thus, there remains in the art the need to identify markers useful in evaluating patient prognosis across the entire spectrum of acute coronary syndromes, so that patients at risk of near-term morbidity or and/or death or can be identified and treated.